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The ORCAS technique highlights the potential value of continuous intracoronary imaging during key procedural steps such as plaque preparation and ostial stent implantation. Real-time IVUS guidance may support more precise assessment and execution, possibly improving procedural accuracy and consistency in complex aorto-ostial lesions, particularly in heavily calcified coronary anatomy.
To assess the prevalence of undiagnosed axial spondyloarthritis (axSpA) in patients attending chiropractic clinics (CCs) with chronic back pain (CBP), using the Assessment of Spondyloarthritis International Society (ASAS) referral strategy. An observational study of adults attending one of four CCs between November 2020-2021 with CBP starting before age of 45, without prior diagnosis of spondyloarthritis (SpA). Patients fulfilling ≥ 1 feature of SpA (Inflammatory back pain [IBP], a family history of SpA, inflammatory bowel disease, psoriasis, good response to NSAIDs, history of heel pain, uveitis, or peripheral arthritis) were referred to rheumatologists. Rheumatology assessment included medical history (telephone interview), laboratory tests (CRP, HLA-B27), x-ray, and MRI of sacroiliac joints. Overall, 3,017 visits in 426 patients were recorded. Seven of the top ten primary complaints were related to spine pain. Of 115 patients referred, 74 were eligible, 59 (79.7%) reported to have IBP. Eight of 65 (12.3%) rheumatologist-assessed patients were diagnosed with SpA [5 (7.7%) as non-radiographic axSpA (nr-axSpA), 1 (1.5%) radiographic axSpA, 1 (1.5%) peripheral SpA (all except 1 fulfilled ASAS classification criteria), and 1 (1.5%) psoriatic arthritis (fulfilled Classification Criteria for Psoriatic Arthritis)]. Objective SpA features (imaging, presence of psoriasis, and positive HLA-B27) had the highest positive likelihood ratio. Twelve percent of patients with CBP referred from CCs using the ASAS referral strategy were found to have undiagnosed SpA, with nr-axSpA being the most common. Further educational efforts and targeted referral strategies in CCs may allow for earlier intervention, improved health outcomes, and cost savings. Key Points • Patients with chronic back pain (CBP) with spondyloarthritis (SpA) features require prompt referral to rheumatologists for early diagnosis and improved treatment outcomes. However, these patients are often overlooked in primary care and chiropractic offices where CBP is initially seen. • The aim of this study was to assess the prevalence of undiagnosed axial spondyloarthritis (axSpA) in patients attending chiropractic clinics with CBP, using the Assessment of Spondyloarthritis International Society (ASAS) referral strategy. • The study found that over 12% of included patients with CPB had undiagnosed SpA and 9% undiagnosed axSpA, with non-radiographic axSpA being the most common. • Educational efforts and targeted referral strategies in chiropractic clinics could improve health outcomes for patients with unrecognized SpA.
Response facilitation has often been portrayed as a "low level" category of social learning, because the demonstrator's action, which is already in the observer's repertoire, automatically triggers that same action, rather than induces the learning of a new action. One way to rule out response facilitation consists of introducing a delay between the demonstrator's behavior and the observer's response to let their possible effects wear off. However, this may not rule out "delayed response facilitation" in which the subject could be continuously "mentally rehearsing" the demonstrated actions during the waiting period. We used a do-as-the-other-did paradigm in two orcas to study whether they displayed cognitive control regarding their production of familiar actions by (1) introducing a delay ranging from 60 to 150 s between observing and producing the actions and (2) interspersing distractor (non-target) actions performed by the demonstrator and by the subjects during the delay period. These two manipulations were aimed at preventing the mental rehearsal of the observed actions during the delay period. Both orcas copied the model's target actions on command after various delay periods, and crucially, despite the presence of distractor actions. These findings suggest that orcas are capable of selectively retrieving a representation of an observed action to generate a delayed matching response. Moreover, these results lend further support to the proposal that the subjects' performance relied not only on a mental representation of the specific actions that were requested to copy, but also flexibly on the abstract and domain general rule requested by the specific "copy command". Our findings strengthen the view that orcas and other cetaceans are capable of flexible and controlled social learning.
Knowledge about parasite species of orcas, their prevalence, and impact on the health status is scarce. Only two records of lungworm infections in orca exist from male neonatal orcas stranded in Germany and Norway. The nematodes were identified as Halocercus sp. (Pseudaliidae), which have been described in the respiratory tract of multiple odontocete species, but morphological identification to species level remained impossible due to the fragile structure and ambiguous morphological features. Pseudaliid nematodes (Metastrongyloidea) are specific to the respiratory tract of toothed whales and are hypothesized to have become almost extinct in terrestrial mammals. Severe lungworm infections can cause secondary bacterial infections and bronchopneumonia and are a common cause of mortality in odontocetes. DNA isolations and subsequent sequencing of the rDNA ITS-2 and mtDNA COI revealed nucleotide differences between previously described Halocercus species from common dolphin (H. delphini) and harbor porpoises (H. invaginatus) that were comparatively analyzed, pointing toward a potentially new species of pseudaliid lungworm in orcas. New COI sequences of six additional metastrongyloid lungworms of seals and porpoises were derived to elucidate phylogenetic relationships and differences between nine species of Metastrongyloidea.
Orca (Orcinus orca) strandings are rare and post-mortem examinations on fresh individuals are scarce. Thus, little is known about their parasitological fauna, prevalence of infections, associated pathology and the impact on their health. During post-mortem examinations of two male neonatal orcas stranded in Germany and Norway, lungworm infections were found within the bronchi of both individuals. The nematodes were identified as Halocercus sp. (Pseudaliidae), which have been described in the respiratory tract of multiple odontocete species, but not yet in orcas. The life cycle and transmission pathways of some pseudaliid nematodes are incompletely understood. Lungworm infections in neonatal cetaceans are an unusual finding and thus seem to be an indicator for direct mother-to-calf transmission (transplacental or transmammary) of Halocercus sp. nematodes in orcas.
Nitroxide-based organic-radical contrast agents (ORCAs) are promising as safe, next-generation magnetic resonance imaging (MRI) tools. Nevertheless, stimuli-responsive ORCAs that enable MRI monitoring of prodrug activation have not been reported; such systems could open new avenues for prodrug validation and image-guided drug delivery. Here, we introduce a novel "pro-ORCA" concept that addresses this challenge. By covalent conjugation of nitroxides and drug molecules (doxorubicin, DOX) to the same brush-arm star polymer (BASP) through chemically identical cleavable linkers, we demonstrate that pro-ORCA and prodrug activation, i.e., ORCA and DOX release, leads to significant changes in MRI contrast that correlate with cytotoxicity. This approach is shown to be general for a range of commonly used linker cleavage mechanisms (e.g., photolysis and hydrolysis) and release rates. Pro-ORCAs could find applications as research tools or clinically viable "reporter theranostics" for in vitro and in vivo MRI-correlated prodrug activation.
Running comparative studies of laterality in mammals is a way to deepen our understanding of the evolution of the brain hemisphere functions. Studies on vision highlighted a possible task-sharing between hemispheres depending on the characteristics of the observers, the nature of the observed stimulus and the context of the observation, a phenomenon that could go beyond the monitoring of conspecifics. Cetaceans are predators that adapted to an aquatic habitat and display a clear crossing of fibers to the side of the brain opposite the eye of origin. Here, we analysed the interactions between humans and cetaceans when free-ranging orcas approach divers. Our study concentrated on the spontaneous exploratory behaviours of divers by orcas depending on their age and sex, and on the possible expression of a visual laterality. The results showed a significant preference for the use of the left eye but exclusively in adult females. Adult males had a more sustained attention than adult females, marked by a higher spatial proximity to divers, slower approaches and longer look durations. Adult females, probably more cautious, explored from the distance and more furtively. Our findings support a possible link between attentional/motivational states and visual laterality in mammals.
The management of socially complex species in captivity is challenging. Research on their social behavior improves our understanding of interactions in captive animals and captive-group management. We conducted a detailed analysis of social relationships shown by the orcas kept at Loro Parque zoo and their tendency to reconcile after aggressive episodes. Affiliative interactions were the most frequent social activities compared to agonistic or sexual interactions. Within affiliative behaviors, we documented the pattern "gentle tongue bite", where an animal touches the other's tongue with his teeth but does not bite it. Affiliative interactions between a specific pair of orcas occurred significantly more often than expected by chance, and together with low levels of agonistic interactions, indicated particular affinity between some individuals. The most frequently observed low-level agonistic relationship was that of the two older males (Tekoa-Keto); however, they also showed frequent sexual and affiliative interactions. Sexual-like behaviors (pursuit, mount, and penis between males) were found in both sexes. Finally, the observed corrected conciliatory tendency (31.57%) was within the range described for other primate and cetacean species. This study provides a systematic way to assess social interactions as well as conflict management strategies in cetaceans housed in zoos and zoo-like facilities and may help to improve animal welfare and management of animals in controlled environments.
Tooth damage as a result of oral stereotypies is evident in captive orca, yet little research on the topic exists. This study examines the associations between dental pathology, sex, facility, duration of captivity and other factors in captive orca. We evaluated mandibular and maxillary teeth from dental images of 29 captive orca owned by a US-based theme park. Each tooth was scored for coronal wear, wear at or below gum line and bore holes. Fractured and missing teeth were also noted. Summary statistics described the distribution and severity of pathologies; inferential statistics examined how pathologies differed between sexes, between wild-captured and captive-born orcas and between captive orca at four facilities. We also evaluated how dental pathology and duration of captivity were related. Approximately 24% of whales exhibited "major" to "extreme" mandibular coronal tooth wear, with coronal wear and wear at or below gum line highly correlated. More than 60% of mandibular teeth 2 and 3 exhibited fractures. Bore holes were observed primarily among anterior mandibular teeth, with more than 61% of teeth 2 and 3 bearing evidence of having been drilled. Four of five orca with the highest age-adjusted tooth pathology indices were captive-born. Various dental pathologies were observed across all whales, with pathologies beginning at a young age. Oral stereotypies exhibited by captive orca contributed to the observed dental damage. By making dental and health records of captive whales publicly available, the theme park industry is uniquely positioned to provide further insight into dental pathology and resultant health consequences in captive orca.
Magnetic resonance imaging (MRI) is one of the most powerful non-invasive methods for cancer diagnostics. To enhance image contrast and, therefore, diagnostic accuracy, contrast agents (CAs) are widely used in clinics. For decades, the clinical standard has been metal-based CAs, primarily gadolinium- and manganese-based chelates, or iron oxide nanoparticles. However, metal-based CAs possess sub-effects, toxicity, and associated adverse health effects, such as nephrogenic systemic fibrosis. As an alternative, metal-free organic radical CAs (ORCAs), based on nitroxides, have been developed. ORCAs are widely used as primary 1H-MRI agents and offer many advantages, including high biocompatibility, biodegradability, and easy functionalization. Attachment of nitroxides to natural or synthetic polymers enables the development of constructs with prolonged systemic circulation time and tumor-targeted delivery. Furthermore, MR-signal amplification can be achieved through physical hyperpolarization techniques, such as dynamic nuclear polarization (DNP) and Overhauser-enhanced MRI (OMRI), in which nitroxide radicals serve as hyperpolarizing agents, yielding signal enhancements. This review summarizes low-molecular-weight nitroxides, polymeric, and biomacromolecular platforms for 1H-MRI, focusing on physicochemical properties, preclinical evidence in tumor imaging, and current limitations. One section highlights the use of nitroxides as hyperpolarizing agents for tumor metabolism analysis or OMRI. The review addresses ongoing challenges and outlines future perspectives for the clinical translation of ORCAs in cancer diagnostics.
Cardiac Diffusion Tensor Imaging (cDTI) provides unique insights into myocardial microstructure in-vivo but requires averaging multiple repetitions for adequate signal quality, leading to prohibitively long acquisition times. Standard acceleration strategies, such as reducing repetitions and employing simultaneous multi-slice (SMS) imaging, are limited by low signal-to-noise ratio (SNR) and inter-slice leakage artefacts, respectively. We introduce ORCAS, a unified framework that synergistically combines a novel variable CAIPIRINHA acquisition with an artefact-aware AI reconstruction to overcome these challenges. The variable CAIPIRINHA scheme decoheres SMS artefacts across repetitions, while our dual-domain deep learning model simultaneously suppresses these artefacts and combats the low SNR from fewer repetitions. The model is guided by patient-specific single-band auxiliary data to preserve anatomical fidelity. Validated on ex-vivo hearts with and without anomalies, ORCAS achieves an over 18-fold acceleration by combining these strategies, reducing a whole-heart scan from over two hours to under 7 min. This is accomplished while reducing errors in key biomarkers, such as Fractional Anisotropy, by up to 64%. The framework preserves essential microstructural properties and the delineation of abnormalities, representing a significant step towards the clinical translation of whole-heart cDTI.
The U.S. Food and Drug Administration (FDA) has issued a boxed warning and mandated additional safety measures for all gadolinium-based contrast agents (GBCAs) used in clinical magnetic resonance imaging (MRI) due to their prolonged retention in the body and associated adverse health effects. This review explores recent advancements in CAs for MRI, highlighting four innovative probes: ORCAs, CEST CAs, 19F CAs, and HP 13C MRI. ORCAs offer a metal-free alternative that enhances imaging through nitroxides. CEST MRI facilitates the direct detection of specific molecules via proton exchange, aiding in disease diagnosis and metabolic assessment. 19F MRI CAs identify subtle biological changes, enabling earlier detection and tailored treatment approaches. HP 13C MRI improves visualization of metabolic processes, demonstrating potential in cancer diagnosis and monitoring. Finally, this review concludes by addressing the challenges facing the field and outlining future research directions, with a particular focus on leveraging artificial intelligence to enhance diagnostic capabilities and optimize both the performance and safety profiles of these innovative CAs. STATEMENT OF SIGNIFICANCE: The review addresses the urgent need for safer MRI contrast agents in light of FDA warnings about GBCAs. It highlights the key factors influencing the stability and functionality of metal-free CAs and recent advancements in designing ORCAs, CEST CAs, 19F CAs, and HP 13C probes and functionalization that enhance MRI contrast. It also explores the potential of these agents for multimodal imaging and targeted diagnostics while outlining future research directions and the integration of artificial intelligence to optimize their clinical application and safety. This contribution is pivotal for driving innovation in MRI technology and improving patient outcomes in disease detection and monitoring.
Free light chain kappa (FLCκ) have emerged as a sensitive biomarker to detect intrathecal immunoglobulin synthesis. To evaluate the role of FLCκ in routine cerebrospinal fluid laboratory diagnostics we conducted a prospective nationwide real world diagnostic study for evaluating the integration of kappa free light chain into clinical routine (ORCAS - prospective multicenter validation of a new laboratory workflow integrating the free light chains kappa in CSF analysis). To determine whether testing for intrathecal synthesis of FLCκ in cerebrospinal fluid (CSF) can predict intrathecal immunoglobulin (Ig) synthesis of total IgG, IgA, IgM or CSF-specific oligoclonal bands (OCB) with high sensitivity. FLCκ were measured in 1052 paired CSF and serum samples according to local laboratory standards in six laboratories in Germany. Sensitivity and negative predictive value (NPV) of intrathecal FLCκ synthesis as first line detection of intrathecal Ig synthesis were assessed. Of the 1052 samples, 624 fulfilled the inclusion criteria. The intrathecal fraction of FLCκ predicted intrathecal Ig synthesis with a sensitivity of 0.87 (CI 0.81-0.93) and a NPV of 0.97 (CI 0.95-0.98). The sensitivity for predicting CSF-specific OCB was 0.93 (CI 0.88-0.98). In the real world setting this study analyzing FLCk for detecting intrathecal Ig synthesis did not reach its prespecified primary endpoint of sensitivity >0.95. Therefore, FLCκ should not yet be introduced as a stand-alone preselection marker for intrathecal Ig synthesis, but may provide additional value when combined with established diagnostic parameters.
The base excision repair enzyme 8-oxoguanine DNA glycosylase 1 (OGG1) plays a central role in maintaining genome integrity and mediating cellular responses to oxidative stress. As such, it represents an attractive target for pharmaceutical modulation. Small-molecule organocatalytic switches (ORCAs) greatly enhance the rate of OGG1-catalyzed cleavage of DNA abasic sites, thereby accelerating DNA repair. Here, we present the discovery and hit-to-lead optimization of a novel class of highly potent serotonin-derived ORCAs with greatly improved pharmacokinetic properties. Biochemical assays, X-ray crystallography, and molecular dynamics simulations point toward a water-mediated mechanism of activation, distinct from previously proposed Brønsted base-assisted models. These findings establish serotonin-based ORCAs as promising chemical probes and potential leads for therapeutic modulation of OGG1 in oxidative stress-driven diseases.
Essential and non-essential elements can harm marine wildlife and impact ecosystems. Using liver (n = 35) and kidney (n = 17) samples from 35 animals from three distinct killer whale (Orcinus orca) ecotypes (fish-eating residents, mammal-eating transients, and offshore shark-eating specialists) stranded from California to Alaska and Hawaii, we determined elemental concentrations (arsenic (As), barium (Ba), beryllium (Be), calcium (Ca), cadmium (Cd), cobalt (Co), copper (Cu), chromium (Cr), iron (Fe), mercury (Hg), methylmercury (MeHg), manganese (Mn), molybdenum (Mo), magnesium (Mg), nickel (Ni), lead (Pb), selenium (Se), thallium (Tl), vanadium (V), and zinc (Zn)). Also, we evaluated associations with demographic and genetic factors. Calves had lower Cd than other life stages in kidney and liver tissue. Adult females had higher liver Se than calves and higher total mercury (tHg) in kidney and liver than calves. Adult males had higher liver Cd, tHg, and Se than calves. Residents had higher liver Mg, Mn, and Mo than transients. Linear regression showed life stage had some effect on the concentration of kidney Hg, and on the concentration of liver Mg, Mn, Mo, Cd, Hg, and Se. A prior study found no microscopic evidence of toxicosis in the tissues of examined animals. Population had some effect on liver Cd and Mg. Mean ± SD Se:Hg molar ratios in kidney (0.871 ± 0.645) and liver (0.932 ± 0.940) were consistent with prior research (at or nearly 1:1), but ratios based on factors varied in kidney. These results expand knowledge of elements in northeastern Pacific killer whales.
8-oxoGuanine DNA glycosylase 1 (OGG1) is the first known target of organocatalytic switches (ORCAs), which rewrite the biochemical function of the enzyme through redirection of its preferred substrate from 8-oxoG to AP sites. Previously, different ORCA chemotypes were shown to enhance the operational pH window for OGG1, possibly through direct involvement in proton transfer events during DNA strand cleavage. Accordingly, compound pKa is a crucial and necessary consideration for the identification and application of future OGG1 ORCAs. Here, we identify a minimal structure of organocatalytic switches-4-anilino pyridines and 6-anilino pyrimidines-which are dimethyl-amino-pyridine (DMAP)-type Brønsted bases binding the active site of OGG1. Systematic interrogation of compound basicity through modulation of electron-withdrawing (EWG) and electron-donating (EDG) substituents reveals that a pKa less or equal to the assay pH is a viable parameter for prediction of compound activity. The lead structure (AC50 13 nM, pKa 7.0) was then identified as a potent scaffold from a screen in a patient-derived 3D model of metabolic dysfunction-associated steatohepatitis (MASH), where it reduced hepatic fibrosis by 35%. Collectively, these findings deepen the knowledge of this novel modulator class, with important implications for future enzyme targets and probe development.
The pituitary gland is central to endocrine regulation in vertebrates, coordinating key physiological processes such as growth, reproduction, and stress responses. In cetaceans, and particularly in large odontocetes like orcas (Orcinus orca), understanding pituitary structure is essential for advancing neuroendocrine research and informing welfare and health assessments. Despite their ecological, cognitive, and conservation significance, detailed morphological studies of the orca pituitary gland remain scarce. In this study, we conducted a comprehensive structural and ultrastructural analysis of the orca pituitary gland using postmortem samples from four captive individuals. We combined computed tomography, histology, immunohistochemistry, and transmission electron microscopy to examine the gland's anatomical organization and cellular composition. Our results reveal features consistent with other cetaceans as well as species-specific characteristics, including the distribution and morphology of endocrine cells within the adenohypophysis and neurohypophysis. These findings provide the first integrated anatomical and ultrastructural reference for the orca pituitary gland, offering valuable insights into cetacean neuroendocrinology and supporting improved species-specific welfare evaluation, health monitoring, and management practices for orcas under human care.
Respiratory rate (mean number of breaths per minute) and respiratory interval (mean time between breaths) can offer insight into a diving mammal's activity state, metabolic rate, behavior, and synchronization due to social cohesion. Also, respiratory rate can reflect an individual animal's health and has the potential to be an informative remotely assessed health metric for monitoring individual animal health in endangered whale species and populations such as southern resident killer whales (Orcinus orca). Using data collected from noninvasive, land-based theodolite tracking, we analyzed swimming speed and surfacing intervals (i.e., mean dive time or mean time between breaths) from 20,613 surfacings of 98 individuals from two populations of the fish-eating, resident killer whale ecotype, namely, one growing (northern resident) and one declining and endangered (southern resident) population. Focal animal sampling was used to measure behavior of individuals of known age and sex in various activity states. Our objective was to evaluate variability and generate normal ranges for respiratory intervals and swimming speeds for killer whales of the Northeast Pacific Ocean resident, fish-eating ecotype to identify baseline respiratory intervals. We found that median respiratory intervals for fish-eating killer whales were between 26 and 29 s for all activity states and that swimming speeds varied by activity state. Median swimming speeds were similar for foraging and traveling (1.6 and 1.7 m/s, respectively), but were significantly slower during resting (1.1 m/s) and social activity (1.3 m/s) states. Three southern resident killer whales in poor body condition (had body condition scores in the lowest 20th percentile of the population) swam at reduced speeds and had shorter median respiratory intervals than outwardly healthy whales of similar age and sex. Respiratory rates, respiratory intervals, and swimming speeds are valuable remotely sensed metrics of health for free-swimming killer whales, especially when combined with other metrics as is the standard in veterinary examinations.